The overarching goal of this proposal is to synthesize and evaluate cyclic polymers for applications in anticancer nanomedicine. Cyclic polymers have unique structural characteristics that may unlock new approaches and knowledge for anticancer therapeutics, particularly with regard to their uptake, retention, and biodegradability. Since state-of-the-art cyclic polymer synthesis still suffers many limitations, a major portion of the proposed work focuses on advancements in catalyst design. Generation of cyclic polymers functionalized for biological applications requires the design and synthesis of new Ru-alkylidene catalysts, as well as the corresponding carbo- and heterocyclic monomers, which will be functionalized to allow conjugation of antitumor drugs. A key advantage of using the proposed metathesis-based polymerizations is that the same monomer pool can be used to provide exact linear analogues of the cyclic polymers for comparative analysis. Ultimately, polymer topology will be evaluated for its effects on the efficacy of nanomedicines for anticancer therapeutics. Finally, the polymers will be made available such that the attached drug bioavailability, uptake into tumor cells, cellular localization, and permeability and retention may be evaluated and quantified in collaboration with the Caltech/UCLA MSB Cancer Center. Specific Aims: 1) To prepare catalysts for the synthesis of cyclic polymers with narrow polydispersities and controlled molecular weights 2) To prepare water-soluble, cyclic catalysts and polymers 3) To synthesize cyclic polymers with biologically relevant pendant substituents 4) To provide cyclic polymer-drug conjugates for biological testing and evaluation of the effects of polymer topology on antitumor therapeutic behavior. PUBLIC HEALTH RELEVANCE Macromolecules are a promising new approach for treating cancer. Size and topology have been identified as key factors impacting the performance of these nanomedicines. We seek to provide cyclic polymers, an unprecedented class of nanomedicines that may have improved performance for anticancer therapeutics.